ROLE OF MYC IN HEPATOCELLULAR PROLIFERATION AND HEPTOCARCINOGENESIS: The oncogene Myc is involved in cell growth, proliferation, apoptosis, energy metabolism, and differentiation. However, its role in is hepatocellular proliferation and carcinogenesis is unclear due to a lack of an efficient hepatocyte-specific Myc disruption model. To investigate the involvement of Myc in hepatocellular proliferation and hepatocarcinogenesis in mice, a temporal hepatocyte-specific Myc knockout mouse line was developed by use of the tamoxifen-inducible Cre-ER(T2) recombinase system in which the modified Cre recombinase cassette was placed under control of the serum albumin promoter. Hepatocyte proliferation was assessed by administering peroxisome proliferator-activated receptor alpha (PPARalpha) agonist Wy-14,643. A diethylnitrosamine-induced liver cancer model was used to evaluate the role of Myc in hepatocarcinogenesis. Tamoxifen administration induced recombination of Myc specifically in hepatocytes of Myc(fl/fl,ERT2-Cre) mice. When treated with the PPARalpha activator and hepatocellular proliferative stimulus Wy-14,643, Myc(fl/fl,ERT2-Cre) mice showed a lower liver/body weight ratio and suppressed hepatocyte proliferation as compared to the control Myc(fl/fl) mice. Hepatic expression of cell cycle control genes, DNA repair genes, and Myc target gene miRNAs were upregulated in Wy-14,643-treated Myc(fl/fl) mouse livers, but not in Wy-14,643-treated Myc(fl/fl,ERT2-Cre) livers. However, no differences were observed in the lipid-lowering effect of Wy-14,643 between Myc(fl/fl,ERT2-Cre) and Myc(fl/fl) mice, consistent with no differences in the expression of several PPARalpha target genes involved in fatty acid beta-oxidation. Moreover, when subjected to the diethylnitrosamine liver cancer bioassay, Myc(fl/fl,ERT2-Cre) mice exhibited a markedly lower incidence of tumor formation compared with Myc(fl/fl) mice. MICROBIOME REMODELING LEADS TO INHIBITION OF INTESTIAL FARNESOID X RECEPTOR SIGNALING AND DECREASED OBESITY: Obesity and type 2 diabetes (insulin resistance) are risk factors for cancer. Obese patients are at increased risk for cancer and obese cancer patients have increased mortality. The antioxidant tempol was previously found to reduce obesity in mice, but its mechanism of action has remained a mystery. Clues to its mechanism emerged when urinary metabolites were found to change upon tempol treatment that result from gut bacterial metabolism. In the current study, a combination of 16S rRNA gene sequencing and mass spectrometry-based metabolomics was used to investigate changes in the gut microbiome and metabolites in a high-fat diet (HFD)-fed mouse model undergoing tempol treatment. Further, intestine-specific Fxr-null (Fxr-deltaIE) mice were employed to explore the mechanism by which the gut microbiome influences obesity and insulin resistance. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-beta-muricholic acid (T-beta-MCA), which sas found to be an antagonist of the FXR nuclear receptor. FXR is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signaling in the intestine. High-fat diet-fed Fxr(deltaIE) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in Fxr(deltaIE) mice, thus suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signaling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs. METABOLOMIC AND LIPIDOMIC ANALYSIS OF LIPID AND MILE ACID MARKERS LINKED TO OBEISTY AND TYPE 2 DIABETES IN MICE. Obesity and type 2 diabetes (insulin resistance) are risk factors for cancer. Obese patients are at increased risk for cancer and obese cancer patients have increased mortality. The antioxidant tempol reduces obesity in mice. Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to HFD-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tg mice. Metabolomics analysis identified 13 metabolites in bile acid synthesis including taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and T-beta-MCA that differed between CYP7A1-tg and wild-type mice. Notably, T-beta-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12alpha-hydroxylated bile acids and increasing intestinal T-beta-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity. HEPATIC OXIDATIVE STRESS ACTIVATES THE GADD45B GENE BY WAY OF DEGRADATION ON THE TRANSCRIPTIONAL REPRESSOR STAT3: Growth arrest and DNA damage-inducible beta (GADD45b) plays an important role in many intracellular events, such as cell cycle arrest, DNA repair, cell survival, apoptosis, and senescence. However, its mechanism of transcriptional regulation remains unclear. In this study the mechanism of PPARalpha ligand induction of the Gadd45b gene in mouse liver was investigated. Gadd45b messenger RNA (mRNA) was markedly induced by the PPARalpha agonist Wy-14,643 in wild-type mice but not in Ppara-null mice. Signal transducer and activator of transcription 3 (STAT3) was found to be a repressor of the Gadd45b gene through binding to upstream regulatory elements. The role of STAT3 in control of Gadd45b was confirmed using liver-specific Stat3-null mice. Wy-14,643 treatment stimulated STAT3 ubiquitination leading to activation of the Gadd45b gene as a result of loss of Gadd45b repression by STAT3. STAT3 degradation was induced by forced overexpression of the PPARalpha target gene-encoded enzyme ACOX1, which produces increased H2O2 as a byproduct of fatty acid beta-oxidation. H2O2 also stimulated expression of Gadd45b in cultured cells. PPARalpha indirectly induces the Gadd45b gene in liver through promoting degradation of the repressor STAT3 as a result of elevated oxidative stress.